This is the first resubmission of an R01 application, 1 R01 DA14419-01, that is a response to a PA (97-043) encouraging research on the origins and pathways to substance abuse (SA). A mixed body of evidence suggests that SA is frequently preceded by childhood attention-deficit/hyperactivity disorder (ADHD) and associated comorbid disorders. The aim of this proposal is to test hypotheses about the co-occurrence of SA in ADHD adolescent girls growing up and their high-risk siblings. We are proposing to study a group of girls available from an NIMH funded five year, family-based, controlled follow-up study of girls with ADHD currently underway with a focus on SA. At baseline assessment, we ascertained 140 ADHD and 120 normal control girls from psychiatric and non-psychiatric settings with 464 and 402 first degree biological relatives, respectively. We now propose a five-year study that will re-examine the probands and families five years after their baseline assessment with a particular emphasis on SA, thus capturing these adolescents as they are beginning to pass through the risk for SA. We have two Main Aims: 1) To characterize SA in ADHD girls growing up, and 2) To determine predictors of SA in ADHD girls growing up. In our preliminary work, we have begun to address issues related to the overlap of SA and ADHD in boys and girls that are the focus of the proposed work. We view the proposed extension of our work as an essential step for several reasons: this work will be the first, prospective high risk family-based study of SA in ADHD girls; we will have extensive information on a well characterized group of children ascertained from medical and psychiatric settings spanning five years; and psychiatric comorbidity within ADHD was not excluded allowing analysis of its influence on later SA. Given the high prevalence of ADHD, its related comorbid disorders, and its frequent persistence into adulthood, the proposed study will shed light on ADHD adolescent and young adult females at highest risk for SA. Since ADHD is treatable and identifiable in early years, these data will provide valuable information to formulate prevention interventions. Thus, the research, approach, and goals of this R01 application are consistent with those underscored in the PA and by the Institute of Medicine as being of the highest research priority.